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Heterocyclic compounds
8399451 Heterocyclic compounds
Patent Drawings:

Inventor: Gilmore, et al.
Date Issued: March 19, 2013
Application:
Filed:
Inventors:
Assignee:
Primary Examiner: Chu; Yong
Assistant Examiner:
Attorney Or Agent: Greenblatt; Gary D.
U.S. Class: 514/210.2; 514/236.2; 514/254.03; 514/256; 514/318; 514/326; 514/342; 514/364; 544/138; 544/333; 544/369; 546/194; 546/209; 546/271.1; 548/131; 548/950
Field Of Search: 514/210.2; 514/364; 544/138; 544/333; 546/209; 546/194; 548/131; 548/950
International Class: A61K 31/4245; A61K 31/4439; A61K 31/506; C07D 417/14; C07D 413/14; A61K 31/497; A61K 31/5377; A61K 31/4545; A61K 31/454; C07D 413/04
U.S Patent Documents:
Foreign Patent Documents: WO9605193; WO9806694; WO2004/035538; WO2004/058149; WO2004/071442; WO2004/103279; WO2004/103306; WO2004/103309; WO2004/113330; WO2005/000833; WO2005/032465; WO2005/058848; WO2006/047195; WO2006/088944; WO2006/100631; WO2006/100633; WO2006/115188; WO2006/131336; WO2006/137019; WO2007/024922; WO2007/080542; WO2007/085451; WO2007/091396; WO2007/116866; WO2008/016674; WO2008/023783; WO2008/028937; WO2008/029306; WO2008/029370; WO2008/029371; WO2008/030843; WO2008/035239; WO 2008029370; WO2008/037476; WO2008/064315; WO2008/074820; WO2008/074821; WO2008/076356; WO2008/079382; WO2008/091967; WO2008/114157; WO2009/011850; WO2009/043889; WO2009/043890; WO2009/057079; WO 2009/080663; WO2009/151529; WO2010/041655; WO2010/064707; WO2010/069949; WO2010/072352; WO2010/072712; WO2010/081692; WO2010/085581; WO2010/085582; WO2010/085584; WO2010/113528; WO2010/113796
Other References: Hale et al., Bioorg. Med. Chem. Lett., 14:3501 (2004). cited by applicant.
Sanna et al., J. Biol. Chem., 279:13839 (2004). cited by applicant.
Anliker et al., J. Biol. Chem., 279:20555 (2004). cited by applicant.
Mandala et al., J. Pharmacol. Exp. Ther., 309:758 (2004). cited by applicant.
Brinkman et al., J. Biol. Chem., 277:21453 (2002). cited by applicant.
Mandala et al., Science, 296:346 (2002). cited by applicant.
Fujino et al., J. Pharmacol. Exp. Ther., 305:70 (2003). cited by applicant.
Brinkmann et al., Am. J. Transplant., 4:1019 (2004). cited by applicant.
Webb et al., J. Neuroimmunol., 153:108 (2004). cited by applicant.
Morris et al., Eur. J. Immunol., 35:3570 (2005). cited by applicant.
Chiba, Pharmacology & Therapeutics, 108:308 (2005). cited by applicant.
Kahan et al., Transplantation, 76:1079 (2003). cited by applicant.
Kappos et al., N. Engl. J. Med., 355:1124 (2006). cited by applicant.
Koyrakh et al., Am. J. Transplant., 5:529 (2005). cited by applicant.
Hale et al., J. Med. Chem., 47:6662 (2004). cited by applicant.
Rosen et al., Trends Immunol., 28:102 (2007). cited by applicant.
International Search Report dated Nov. 24, 2010. cited by applicant.









Abstract: Disclosed are compounds of Formula (I) ##STR00001## or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: A is ##STR00002## Q is a substituted 5-membered monocyclic heteroaryl group; W is CH.sub.2, O, or NH; and R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, m, n, t, and x are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P.sub.1, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.
Claim: What is claimed is:

1. A compound of Formula (I): ##STR00333## or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: m is 1 or 2; n is 1 or 2; wherein: W is CH.sub.2 when(m +n) is 2 or 3; or W is CH.sub.2, O, or NH when (m +n) is 4; R.sub.1 is --(CR.sub.dR.sub.d).sub.aOH, --(CR.sub.dR.sub.d).sub.aCOOH, --(CR.sub.dR.sub.d).sub.aC(O)NR.sub.cR.sub.c, --(CR.sub.dR.sub.d).sub.aC(O)NHS(O).sub.2(C.sub.1-3alkyl),--(CR.sub.dR.sub.d).sub.aC(O)NHS(O).sub.2(aryl), or --(CR.sub.dR.sub.d).sub.atetrazolyl; each R.sub.2 is independently halo, C.sub.1-4alkyl, C.sub.1-2haloalkyl, --OH, C.sub.1-3alkoxy, and/or --NR.sub.cR.sub.c; R.sub.3 and R.sub.4 are independently Hand/or C.sub.1-6alkyl; or R.sub.3 and R.sub.4 together with the carbon atom to which they are attached, form a 3- to 6-membered ring containing zero or 1 heteroatom selected from O and N; R.sub.5 is H or C.sub.1-4alkyl; each R.sub.6 is independentlyC.sub.1-3alkyl, halo, C.sub.1-3haloalkyl, --CN, --OH, C.sub.1-3alkoxy, and/or C.sub.1-3haloalkoxy; A is ##STR00334## Q is a 5-membered monocyclic heteroaryl group having 1 to 3 heteroatoms independently selected from N, O, and S, wherein said heteroarylgroup is substituted with R.sub.a and zero or 1 R.sub.b, provided that Q is not 2-furan-2-yl, 4-thiazolyl, 4-oxazolyl, or 1,2,3-triazolyl; R.sub.ais C.sub.2-6alkyl, C.sub.2-4haloalkyl, C.sub.3-6cycloalkyl, tetrahydropyranyl, or a cyclic group selectedfrom phenyl, benzyl, and 5- to 6-membered monocyclic heteroaryl groups having 1 to 3 heteroatoms independently selected from N, O, and S, wherein said cyclic group is substituted with zero, 1, 2, or 3 substituents independently selected from halo, --CN,--OH, C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-3haloalkyl, and C.sub.1-2haloalkoxy; R.sub.b is C.sub.1-3alkyl or C.sub.1-3haloalkyl, provided that if R.sub.a is alkyl then R.sub.b is C.sub.1-3haloalkyl; each R.sub.c is independently H and/orC.sub.1-4alkyl; each R.sub.d is independently H, --OH, C.sub.1-4alkyl, C.sub.1-4haloalkyl, and/or C.sub.1-4alkoxy; a is zero, 1, 2, or 3; t is zero, 1, 2, 3, or 4; and x is zero, 1, or 2; with the proviso that the following compounds are excluded:##STR00335##

2. The compound according to claim 1 or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R.sub.3 and R.sub.4 are independently H and/or C.sub.1-4alkyl; R.sub.a is C.sub.2-4alkyl, C.sub.2-3fluoroalkyl, C.sub.4-6cycloalkyl,tetrahydropyranyl, or a cyclic group selected from phenyl, benzyl, and 5- to 6-membered monocyclic heteroaryl groups having 1 to 2 heteroatoms independently selected from N, O, and S, wherein said cyclic group is substituted with zero, 1, 2, or 3substituents independently selected from halo, --CN, C.sub.1-4alkyl, C.sub.1-3alkoxy, --CF.sub.3, and --OCF.sub.3; R.sub.b is C.sub.1-3alkyl or --CF.sub.3, provided that if R.sub.a is C.sub.2-4alkyl then R.sub.b is --CF.sub.3; and each R.sub.d isindependently H, --OH, and/or --CH.sub.3.

3. The compound according to claim 1 or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R.sub.1 is --(CR.sub.dR.sub.d).sub.aOH, --(CR.sub.dR.sub.d).sub.aCOOH, or --C(O)NR.sub.cR.sub.c; each R.sub.2 is independently F,Cl, --OH, and/or C.sub.1-4alkyl; each R.sub.6 is independently C.sub.1-2alkyl, F, Cl, C.sub.1-2haloalkyl, --CN, --OH, C.sub.1-2alkoxy, and/or C.sub.1-2haloalkoxy; R.sub.ais C.sub.2-4alkyl, C.sub.2-3fluoroalkyl, cyclohexyl, tetrahydropyranyl, or acyclic group selected from phenyl, benzyl, and 5- to 6-membered monocyclic heteroaryl groups having 1 to 2 heteroatoms independently selected from N, O, and S, wherein said cyclic group is substituted with zero, 1, 2, or 3 substituents independentlyselected from halo, --CN, C.sub.1-4alkyl, C.sub.1-2alkoxy, --CF.sub.3, and --OCF.sub.3; each R.sub.d is independently H, --OH, C.sub.1-2alkyl, C.sub.1-3fluoroalkyl, and/or C.sub.1-2alkoxy; and t is zero, 1, 2, or 3.

4. The compound according to claim 1 or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Q is a heteroaryl group selected from thiophenyl, pyrazolyl, isoxazolyl, 5-thiazolyl, imidazolyl, and isothiazolyl, wherein saidheteroaryl group is substituted with R.sub.a and zero or 1 R.sub.b.

5. The compound according to claim 1 having formula (Ie): ##STR00336## or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R.sub.1 is --CH.sub.2OH, --CH.sub.2CH.sub.2OH, --(CH.sub.2).sub.aCOOH, --C(CH.sub.3).sub.2COOH, or--C(O)N(ethyl).sub.2; R.sub.2 is F, --OH, or --CH.sub.3; R.sub.3 and R.sub.4 are independently H and/or --CH.sub.3; R.sub.5 is H or --CH.sub.3 R.sub.6 is --CF.sub.3; Q is a heteroaryl group selected from thiophenyl, pyrazolyl, isoxazolyl,5-thiazolyl, imidazolyl, and isothiazolyl, wherein said heteroaryl group is substituted with R.sub.a and zero or 1 R.sub.b; R.sub.ais C.sub.3-4alkyl, --CH.sub.2CF.sub.3, cyclohexyl, tetrahydropyranyl, or a cyclic group selected from phenyl, pyridinyl,and pyrimidinyl, wherein said cyclic group is substituted with zero to 2 substituents independently selected from F, Cl, Br, C.sub.1-3alkyl, --CF.sub.3,and --OCH.sub.3; R.sub.b is C.sub.1-3alkyl or --CF.sub.3, provided that if R.sub.a is C.sub.3-4alkylthen R.sub.b is --CF.sub.3; a is zero, 1, or 2; t is zero or 1; and x is zero or 1.

6. The compound according to claim 5 or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R.sub.1 is --(CH.sub.2).sub.aOH, --(CH.sub.2).sub.aCOOH, --C(CH.sub.3).sub.2COOH, or --C(O)N(ethyl).sub.2; R.sub.2 is F, --OH, or--CH.sub.3; R.sub.3 is H; R.sub.4 is H; R.sub.5 is H or --CH.sub.3; R.sub.6 is --CF.sub.3; and t is zero or 1.

7. The compound according to claim 1 represented by formula (If): ##STR00337## or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R.sub.1 is --(CH.sub.2).sub.aCOOH; and p is 1, 2, or 3.

8. The compound according to claim 7 represented by formula (If): ##STR00338## or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R.sub.1 is --(CH.sub.2).sub.aCOOH; and p is 1, 2, or 3.

9. The compound according to claim 8 represented by formula (Ig): ##STR00339## or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R.sub.1 is --(CH.sub.2).sub.aCOOH; and a is zero, 1, or 2.

10. The compound of claim 1 or a salt thereof, wherein said compound is selected from: 1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)- 1 ,2,4-oxadiazol-3-yl) phenyl)ethyl)azetidine-3-carboxylic acid (1); 1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-y- l)phenyl)ethyl)piperidine-2-carboxylic acid (2); 1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-y- l) phenyl)ethyl)piperidine-3-carboxylic acid (3); (3S)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazo- l-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid (4); (3R)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazo- l-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid(5); 1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-y- l)phenyl)ethyl)pyrrolidine-3-carboxylic acid (6); (2R)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazo- l-3-yl)phenyl)ethyl)azetidine-2-carboxylic acid(7); 2-(1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-- 3-yl)phenyl)ethyl)piperidin-2-yl)acetic acid (8 and 9); 2-((2S)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadi-azol-3-yl)phenyl)ethyl)pyrrolidin-2-yl)acetic acid (10); 4-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl1)-1,2,4-oxadiazol-3-- yl)phenyl)ethyl) morpholine-2-carboxylic acid (11); 2-((3S)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadi- azol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid (12); 2-((3R)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadi- azol-3-yl)phenyl)ethyl)piperidin-3-yl)aceticacid (13); (S)-1-(S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1- ,2,4-oxadiazol-3-yl)phenyl)ethyl) piperidine-3-carboxylic acid (14); (S)-1-(R)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1-,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid (15); (3S)-1-(2-hydroxy-2-(4-(5-(3-(pyridin-2-yl)-4-(trifluoromethyl) isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid (16); (3S)-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2- ,4-oxadiazol-3-yl)phenyl)propyl)piperidine-3-carboxylic acid (17); 2-((3R)-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)--1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid (18 and 19); (3S)-1-(2-hydroxy-2-(4-(5-(5-isobutyl-4-(trifluoromethyl)isoxazol-3-yl)-1- ,2,4-oxadiazol-3-yl)phenyl)ethyl) piperidine-3-carboxylic acid (20); 4-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-y- l)phenyl)ethyl)piperazine-2-carboxylic acid (21); 2-(1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-- 3-yl)phenyl)ethyl) piperidin-3-yl)acetic acid (22); 1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-y- l)phenyl)ethyl)piperidin-3-ol (23); N,N-diethyl-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-o- xadiazol-3-yl)phenyl)ethyl) piperidine-3-carboxamide (24); 1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl) isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)azetidine-3-carboxylic acid (25); (3S)-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2-,4-oxadiazol-3-yl)-3-(trifluoromethyl)phenyl)ethyl)piperidine-3-carboxylic acid (26); 2-(1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4- -oxadiazol-3-yl)phenyl)ethyl)azetidin-3-yl)acetic acid (27); 4-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-ox- adiazol-3-yl)phenyl)ethyl)morpholine-2-carboxylic acid (28); 2-(4-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4--oxadiazol-3-yl)phenyl)ethyl)morpholin-3-yl)acetic acid (29); 2-(3-(hydroxymethyl)piperidin-1-yl)-1-(4-(5-(3-phenyl-4-(trifluoromethyl)- isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol (30); 2-(3-(2-ydroxyethyl)piperidin-1-yl)-1-(4-(5-(3-phenyl-4-(trifluoromethyl)- isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol (31); 5-hydroxy-1-(2-hydroxy -2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl-)phenyl)ethyl)piperidine-3-carboxylic acid (32); 2-(4-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4- -oxadiazol-3-yl)phenyl)ethyl)morpholin-2-yl)acetic acid (33); 3-fluoro-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)- -1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid (34); 2-((3R)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid (35); (3S)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2- ,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid (36); (3S)-1-(2-hydroxy-2-(4-(5-(3-(6-methylpyridin-2-yl)-4-(trifluoromethyl)is- oxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid (37); 1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-ox-adiazol-3-yl)phenyl)ethyl)-3-methylpiperidine-3-carboxylic acid (38); 3-hydroxy-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl- )-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid (39); 3-(1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4- -oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)propanoic acid (40); (2R)-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2-,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-2-carboxylic acid (41); 1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-ox- adiazol-3-yl)phenyl)ethyl)-6-methylpiperidine-2-carboxylic acid (42); (3S)-1-(2-hydroxy-2-(4-(5-(5-(pyridine-2-yl)thiophen-2-yl)-1,2,4-oxadiazo- l-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid (43); (3S)-1-(2-hydroxy-2-(4-(5-(1-phenyl-5-propyl -1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxyl- icacid (44); (3S)-1-(2-hydroxy-2-(4-(5-(5-methyl-1-phenyl-1H-pyrazol-3-yl)-1,2,4-oxadi- azol-3-yl)phenyl)ethyl) piperidine-3-carboxylic acid (45); (3S)-1-(2-hydroxy-2-(4-(5-(4-methyl-2-phenylthiazol-5-yl)-1,2,4-oxadiazol--3-yl)phenyl)ethyl)piperidine-3-carboxylic acid (46); (3S)-1-(2-hydroxy-2-(4-(5-(1-phenyl -1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl) phenyl)ethyl)piperidine-3-carboxylic acid (47); (3S)-1-(2-(4-(5-(3-(4-chlorophenyl)-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl-)phenyl)-2-hydroxyethyl)piperidine-3-carboxylic acid (48); (3S)-1-(2-(4-(5-(3-(2-chlorophenyl)-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl- )phenyl)-2-hydroxyethyl)piperidine-3-carboxylic acid (49); (3S)-1-(2-hydroxy-2-(4-(5-(1-methyl-3-phenyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl) ethyl)piperidine-3-carboxylic acid (50); (3S)-1-(2-(4-(5-(5-ethyl-1-(pyridin-2-yl)-1H-pyrazol-4-yl)-1,2,4-oxadiazo- l-3-yl)phenyl)-2-hydroxyethyl)piperidine-3-carboxylic acid (51); (3S)-1-(2-hydroxy-2-(4-(5-(5-methyl-1-phenyl- 1H -pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid (52); (3S)-1-(2-(4-(5-(5-(4-chlorophenyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)ph- enyl)-2-hydroxyethyl)piperidine-3-carboxylicacid (53); 2-((3R)-1-(2-hydroxy-2-(4-(5-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazo- l-5-y1)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl) acetic acid (54); (3S)-1-(1-hydroxy-2-methyl -1-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propan-2-yl)piperidine-3-carbo- xylic acid, TFA (55); 2-((3R)-1-(2-hydroxy-2-(4-(5-(3-(pyridin-2-yl)-4-(trifluoromethyl) isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid (56); (S)-1-((S)-2-hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-y- l)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid (57); 2-((R)-1-((S)-2-hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol--4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid, HCl (58); 2-((R)-1-((S)-2-(4-(5-(1-cyclohexyl-5-(trifluoromethyl)-1H-pyrazol-- 4-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl)piperidin-3-yl)acetic acid, HCl(59); 2-((3R)-1-((2S)-2-(4-(5-(1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-- pyrazol-4-yl)-1,2,4-oxadiazol-3-yl) phenyl)-2-hydroxyethyl)piperidin-3-yl)acetic acid, TFA (60); 2-((R)-1-((S)-2-(4-(5-(1-(6-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl) phenyl)-2-hydroxyethyl)piperidin-3-yl)acetic acid, HCl(61); 2-((R)-1-((S)-2-(4-(5-(1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl)piperidin-3-yl)acetic acid, HCl(62); 2-((R)-1-((S)-2-(4-(5-(1-(3-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-- 4-yl)-1,2,4-oxadiazol-3-yl)phenyl) -2-hydroxyethyl)piperidin-3-yl)acetic acid, HCl(63); 2-((R)-1-((S)-2-hydroxy-2-(4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-- pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl) ethyl)piperidin-3-yl)acetic acid, tetrabutylammonium salt (64); 2-((R)-1-((S)-2-(4-(5-(1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl) phenyl)-2-hydroxyethyl)piperidin-3-yl)acetic acid (65); 2-((R)-1-((S)-2-(4-(5-(1-(4-bromophenyl)-5-(trifluoromethyl)-1H-pyrazol-4- -yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl)piperidin-3-yl)acetic acid (66); 2-((R)-1-((S)-2-hydroxy-2-(4-(5-(1-m -tolyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)e- thyl) piperidin-3-yl)acetic acid, HCl(67); 2-((3R)-1-((2S)-2-hydroxy-2-(4-(5-(1-(2-methoxyphenyl)-5-(trifluoromethyl- )-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)aceti- c acid (68); 2-((R)-1-((S)-2-hydroxy-2-(4-(5-(1-(tetrahydro-2H-pyran-4-yl)-5-(trifluor- omethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl- )acetic acid (69); 2-((R)-1-((S)-2-(4-(5-(1-(5-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-py- razol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl) piperidin-3-yl)acetic acid, HCl(70); 2-((R)-1-((S)-2-hydroxy-2-(4-(5-(1-(2,2,2-trifluoroethyl)-5-(trifluoromet-hyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl) ethyl)piperidin-3-yl)acetic acid, HCl(71); 2-((3R)-1-((2S)-2-(4-(5-(1-(2-chlorophenyl)-5-(trifluoromethyl)-1H -pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl)piperidin-3-yl- )acetic acid,HCl(72); 2-((3R)-1-((2S)-2-(4-(5-(1-(2,4-difluorophenyl)-5-(trifluoromethyl)-1H-py- razol-4-yl)-1,2,4-oxadiazol -3-yl)phenyl)-2-hydroxyethyl)piperidin-3-yl)acetic acid, HCl(73); 2-((3R)-1-((2S)-2-hydroxy-2-(4-(5-(5-(trifluoromethyl)-1-(2-(trifluoromet-hyl)phenyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-y1)phenyl)ethyl)piperidin-3- -yl)acetic acid, HCl(74); 2-((R)-1-(S)-2-hydroxy-2-(4-(5-(5-(trifluoromethyl)-1-(3-(trifluoromethyl- )phenyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl-)acetic acid, HCl(75); 2-((R)-1-(S)-2-hydroxy-2-(4-(5-(5-(trifluoromethyl)-1-(4-(trifluoromethyl- )phenyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl- )acetic acid (76); 2-((3R)-1-((2S)-2-hydroxy-2-(4-(5-(1-o-tolyl-5-(trifluoromethyl)-1H-pyraz- ol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid (77); 2-((R)-1-((S)-2-hydroxy-2-(4-(5-(1-p-tolyl-5-(trifluoromethyl)-1H-p-yrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid (78); 2-((R)-1-((S)-2-hydroxy-2-(4-(5-(1-(4-isopropylphenyl)-5-(trifluoro- methyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl) phenyl)ethyl)piperidin -3-yl)acetic acid (79); 2-((R)-1-((S)-2-hydroxy-2-(4-(5-(1-(4-methoxyphenyl)-5-(trifluoromethyl) -1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl) ethyl)piperidin-3-yl)acetic acid (80); 2-((R)-1-((S)-2-hydroxy-2-(4-(5-(1-isobutyl-5-(trifluoromethyl)-1H-pyrazo-l-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid, HCl(81); 2-((R)-1-((S)-2-(4-(5-(1-(5-fluoropyridin-2-yl) -5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydr- oxyethyl) piperidin-3-yl)acetic acid, HCl(82); 2-((3R)-1-((2S)-2-(4-(5-(1-(5-chloro-3-fluoropyridin-2-yl)-5-(trifluorome- thyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl) phenyl)-2-hydroxyethyl)piperidin-3-yl)acetic acid, HCl(83); 2-((3R)-1-((2S)-2-(4-(5-(1-(5-ethoxy-3-fluoropyridin-2-yl)-5-(trifluorome- thyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl)piperid- in-3-yl)acetic acid, HCl(84); 2-((R)-1-((S)-2-hydroxy-2-(4-(5-(1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid (85); 2-((R)-1-((S)-2-hydroxy-2-(4-(5-(1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-- pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid (86); 2-((R)-1-((S)-2-hydroxy-2-(4-(5-(5-(trifluoromethyl)-1-(5-(trifluor- omethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)p- iperidin-3-yl)acetic acid, HCl(87); 2-((3R)-1-((2S)-2-(4-(5-(1-(3,5-dichloropyridin-2-yl)-5-(trifluoromethyl)- -1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl)piperidin-3-- yl)acetic acid, HCl(88); 2-((3R)-1-((2S)-2-(4-(5-(1-(2,4-dichlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydr- oxyethyl)piperidin-3-y1)acetic acid, HCl(89); 2-((3R)-1-((2S)-2-(4-(5-(1-(4-chloro-2-methylphenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl)piperidin-3- -yl)acetic acid, HCl(90); 2-((R)-1-((S)-2-(4-(5-(1-(4-chloro-3-methylphenyl)-5-(trifluoromethyl)-1H- -pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl)piperidin-3-yl)-acetic acid, HCl(91); 2-((R)-1-((S)-2-(4-(5-(1-(3,4-dichlorophenyl)-5-(trifluoromethyl)-1H-pyra- zol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl)piperidin-3-yl)aceti- c acid, HCl(92); 2-((R)-1-((S)-2-hydroxy-2-(4-(5-(1-(4-methylpyridin-2-yl)-5-(trifluoromet- hyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)ace- tic acid, HCl(93); 2-((R)-1-((S)-2-hydroxy-2-(4-(5-(1-(5-methylpyridin-2-yl)-5-(trifluoromet-hyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)ace- tic acid (94); 2-((3R)-1-((2S)-2-(4-(5-(1-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-5-(- trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyet-hyl)piperidin-3-yl)acetic acid (95); 2-((R)-1-((S)-2-hydroxy-2-(4-(5-(1-(6-methyl-4-(trifluoromethyl)pyridin-2- -yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl )phenyl)ethyl)piperidin-3-yl)acetic acid, HCl(96); (S)-1-((S)-2-(4-(5-(1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-y- l)-1,2,4-oxadiazol-3-yl) phenyl)-2-hydroxyethyl)piperidine-3-carboxylic acid, HCl(97); (S)-1-((S)-2-hydroxy-2-(4-(5-(5-(trifluoromethyl)-1-(5-(trifluoromethyl)p-yridin-2-yl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine- -3-carboxylic acid, HCl(98); (S)-1-((S)-2-hydroxy-2-(4-(5-(1-(4-methoxyphenyl)-5-(trifluoromethyl) -1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxyl- icacid, HCl(99); (S)-1-((S)-2-(4-(5-(1-(3,5-dichloropyridin-2-yl)-5-(trifluoromethyl)-1H-p- yrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl)piperidine-3-carb- oxylic acid, HCl(100); (S)-1-((S)-2-(4-(5-(1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyraz- ol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl)piperidine-3-carboxyl- ic acid, HCl(101); (S)-1-((S)-2-hydroxy-2-(4-(5-(1-m-tolyl-5-(trifluoromethyl)-1H-pyrazol-4--yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid (102); (S)-1-((S)-2-hydroxy-2-(4-(5-(1-(5-methylpyridin-2-yl)-5-(trifluoromethyl-

)-1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid (103); (S)-1-((S)-2-hydroxy-2-(4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyr- azol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine -3-carboxylic acid(104); (S)-1-((S)-2-(4-(5-(1-(5-chloropyridin-2-yl)-5-(trifluoromethyl)-1- H -pyrazol-4-yl)-1,2,4-oxadiazol-3-yl) phenyl)-2-hydroxyethyl)piperidine-3-carboxylic acid (105); (S)-1-((S)-2-(4-(5-(1-cyclohexyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2-,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl)piperidine-3-carboxylic acid (106); (S)-1-((S)-2-(4-(5-(1-(2,4-difluorophenyl)-5-(trifluoromethyl)-1H-- pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl)piperidine-3-car- boxylic acid, HCl(107); 2-((R)-1-(S)-2-hydroxy-2-(4-(5-(5-isobutyl-4-(trifluoromethyl)isoxazol -3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl) piperidin-3-yl)acetic acid, TFA (108); 2-((R)-1-((S)-2-(4-(5-(5-tert-butyl-4-(trifluoromethyl)isoxazol-3--yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl) piperidin-3-yl)acetic acid, TFA (109); 2-((R)-1-(S)-2-hydroxy-2-(4-(5-(5-isopropyl-4-(trifluoromethyl)isoxazol-3- -yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid, HCl (110); 2-((R)-1-((S)-2-(4-(5-(5-cyclohexyl-4-(trifluoromethyl) isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl)piperidin-3-yl- )acetic acid, HCl(111); 2-((R)-1-((S)-2-(4-(5-(5-(3-chlorophenyl)-4-(trifluoromethyl)isoxazol-3-y-l)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl)piperidin-3-yl)acetic acid (112); 2-((3R)-1-((2S)-2-(4-(5-(5-(2-chlorophenyl)-4-(trifluoromethyl)iso- xazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl)piperidin-3-yl)ace- tic acid, HCl (113); (S)-1(S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isothiazol-5-yl)-- 1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid, HCl (114); 2-((R)-1-(S)-2-hydroxy-2-(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl-)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid (115); 2-((R)-1-((S)-2-(4-(5-(1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-- 4-yl) -1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl)piperidin-3-yl)acetic acid (116); 2-((R)-1-((S)-2-(4-(5-(1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-imidazol- -4-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl)piperidin-3-yl)acetic acid (117); and 2-((R)-1-(S)-2-hydroxy-2-(4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-i-midazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl) ethyl)piperidin-3-yl)acetic acid (118).

11. A pharmaceutical composition comprising a compound according to claim 1 or stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
Description:
 
 
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